WO2022029785A1 - Oléylcystéinamide ou dérivés de celui-ci et leurs utilisations en thérapie - Google Patents

Oléylcystéinamide ou dérivés de celui-ci et leurs utilisations en thérapie Download PDF

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WO2022029785A1
WO2022029785A1 PCT/IL2021/050955 IL2021050955W WO2022029785A1 WO 2022029785 A1 WO2022029785 A1 WO 2022029785A1 IL 2021050955 W IL2021050955 W IL 2021050955W WO 2022029785 A1 WO2022029785 A1 WO 2022029785A1
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oca
derivative
analogue
clinical
carrier
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PCT/IL2021/050955
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English (en)
Inventor
Simon Benita
Taher Nassar
Riki Perlman
Dina Ben Yehuda
Ihab Abd-Elrahman
Noha KHAIRI
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Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.
Hadasit Medical Research Services & Development Limited
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Application filed by Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd., Hadasit Medical Research Services & Development Limited filed Critical Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.
Priority to US18/040,450 priority Critical patent/US20230293459A1/en
Priority to IL300416A priority patent/IL300416A/en
Priority to AU2021321510A priority patent/AU2021321510A1/en
Priority to JP2023507990A priority patent/JP2024503174A/ja
Priority to CA3190816A priority patent/CA3190816A1/fr
Priority to EP21758474.7A priority patent/EP4192441A1/fr
Priority to CN202180067249.2A priority patent/CN116437907A/zh
Publication of WO2022029785A1 publication Critical patent/WO2022029785A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
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    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the invention generally concerns novel adjuvants and anti-inflammatory agents and uses thereof.
  • Immunotherapy has emerged as an effective strategy for the prevention and treatment of a variety of diseases, including cancer, infectious diseases, inflammatory diseases, and autoimmune diseases.
  • immuno stimulatory therapy should be used for the activation of immune response to detect and eliminate non-self-antigens, and to establish memory effects for these diseases.
  • overactive immune response in diseases like atherosclerosis, rheumatoid arthritis (RA), diabetes, obesity, and transplantation, immunosuppressive therapy is needed to downregulate immune reaction and generate certain immune tolerance.
  • the mammalian immune environment can be regulated by a variety of immune cells, cytokines, and enzymes, which shave been shown to control and prevent immune-related disorders or illnesses.
  • Many immunotherapeutic methods have achieved impressive outcomes in treating various diseases, but performances of immunoregulatory agents can be negatively affected by poor solubility, high immune- mediated toxicity, and loss of bioactivity after long circulation.
  • Immunomodulatory agents and drugs incorporated into nano-delivery system have been shown to improve the therapeutic effects and simultaneously overcome many obstacles facing other treatment methods, such as inadequate immune stimulation, off- target side effects, and bioactivity loss of immune agents during circulation.
  • researchers have continuously developed nanomaterials with new structures, properties, and functions.
  • nano-systems have been shown to play an essential role in immune cell activation and tumor microenvironment modulation.
  • infectious diseases many encouraging outcomes from using nanomaterial vaccines against viral and bacterial infections have been reported.
  • nanoparticles have been shown to potentiate the effects of immunosuppressive immune cells for the treatment of inflammatory and autoimmune diseases.
  • OCA Oleylcysteineamide
  • our immune system is able to protect us from a variety of illnesses through a natural 'immune surveillance', by which viruses, bacteria, and cancer cells can be rapidly identified as alien antigens and eliminated by immune cells.
  • successful pathogens have developed a range of effective mechanisms to evade immune clearance by inhibiting phagocytosis, blocking antigen presentation, or directly killing immune cells.
  • cancer cells can alter the tumor microenvironment into a highly immunosuppressive state by recruiting immunosuppressive immune cells and by expressing a series of inhibitory cytokines, enzymes, and checkpoint molecules, thus facilitating tumor immune evasion. These barriers hinder the efficiency and intensity of the natural immune responses.
  • aberrant activation of immune cells can arouse uncontrolled inflammation and cause inflammatory diseases, autoimmune diseases, or allergic diseases. Abnormal inflammation can also lead to transplant rejection and hinder tissue and organ regeneration.
  • Immunomodulators some of which are chemically well-defined and others that are complex preparations, exhibit a great variety of structures and immuno- pharmacological properties. Essentially, these molecules act on a host own immune system to fight immunocompromised conditions, such as cancer and others as above.
  • the present invention is based on the surprising findings of a multipotent immunomodulator capable of both suppression and enhancement of immune response, depending on the chemical context of the molecule.
  • the immuno modulator per se is oleylcysteineamide (OCA).
  • OCA oleylcysteineamide
  • a carrier e.g., poly(lactic glycolic) acid (PLGA) nanoparticles
  • OCA oleylcysteineamide
  • PLGA poly(lactic glycolic) acid
  • the immunomodulatory effects of OCA alone or when bound to a carrier are essentially different in terms of capability to enhance or suppress specific cytokines, thus providing a surprisingly simple and straightforward tool for differential modulation of host immune responses in the context of various clinical conditions.
  • EXAMPLES 1-5 presently demonstrate that the binary system of OCA-carrier (e.g., PLGA nanoparticles, PLGA-NPs) free of any drug agent, induced a stronger immunological response, as per elevated serum Interferon-y (INF-y) levels in mice treated with PLGA-NPs compared to CD40L-NPs: CD40L being a known stimulator of INF-y (Fig. 1).
  • OCA-carrier e.g., PLGA nanoparticles, PLGA-NPs
  • the OCA-carrier system further induced proliferation of specific populations of immune cells, as per complete blood counts (CBC) showing elevated populations of lymphocytes and monocytes and a reduced population of neutrophils in mice treated with OCA- PLGA-NPs compared to PLGA-NPs treated or untreated mice (Fig. 4).
  • CBC complete blood counts
  • the immune-activating effect of the OCA-carrier as manifested in vivo in elevated production of the INF-y cytokine was further accompanied by elevated production of specific populations of immune cells and suppression of other population(s).
  • OCA alone as a free molecule, inhibited the production of several proinflammatory cytokines in LPS-induced macrophage model in vitro, as per reduced production of TNF-a and IL-6 in the OCA treated cells compared to untreated controls (Figs 2-3).
  • the effect was specific and dose dependent and in certain OCA concentrations was comparable to Dexamethasone (DEX).
  • OCA OCA-associated keratinocytes
  • OCA Owing to its intrinsic amphiphilic nature, OCA is a likely candidate to penetrate hydrophilic and lipophilic barriers such as skin and cornea.
  • OCA as an immunomodulator was strictly dependent on its structural context, and while as OCA-carrier it was acting as an immune enhancer, OCA alone exhibited activities characteristic of an anti-inflammatory agent. Overall, OCA allows access to a new type of immunotherapies permitting fine-tuning of the host immune responses.
  • EXAMPLE 6 demonstrates surprising and new topical application of OCA as a whitening agent.
  • Accessible skin lightening is an important unmet need in dermatology.
  • a variety of over-the-counter agents are currently available, including Kojic acid, licorice extract and vitamin C. Many of these agents are achieving depigmentation by inhibiting the activity of tyrosinase, being one of the key enzymes in the melanin biosynthesis (melanogenesis) in the epidermal melanocytes.
  • Kojic acid (5-hydroxymethyl-4H-pyran-4-one), a hydrophilic fungal derivative from Aspergillus and Penicillium sp., is relatively efficient whitening agent but is increasingly becoming controversial.
  • Kojic acid inhibits melanin production by binding to copper and inhibiting tyrosinase activity. Its safety is being questioned and raises considerable concerns, owing to which it is banned in some parts of Asia, for example. In other words, there is a pressing need for safer and more efficient whitening agents.
  • OCA exhibited the potential to inhibit tyrosinase activity to a similar extent as Kojic acid, as per comparative dose response plots and IC50 estimates on tyrosinase activity in cell-free assay (Fig. 8 and Table 1).
  • Fig. 1 illustrates the immunoenhancing effect of the binary OCA-carrier system.
  • Figure shows serum IFN-y levels in mice 29 days following IV injection of lymphoma cells and treatment with OCA-PLGA-NPs, as determined by ELISA.
  • Fig. 2 illustrates the immune-suppressing effect of OCA alone.
  • Figure shows IL- 6 level normalized to viability (%) in RAW macrophage 264.7 cells after LPS induction and treatment with various concentrations of OCA (1 and 2.5 pg/ml) and Dexamethasone (DEX, 5 pg/ml).
  • Fig. 3 illustrates the same effect with the example of TNF-a, using the same system and concentrations of actives.
  • Fig. 4 illustrates the effect of OCA-PLGA-NPs on the proliferation of specific populations of immune cells.
  • the Figure shows the counts of lymphocytes, monocytes and neutrophils in the peripheral blood of mice treated once a week with PLGA-NPs and PLGA-OCA-NPs (total 3 treatments).
  • Figs 5A-5B illustrate the relationship between OCA dose (0.1%, 0.25%, 0.5% and 1%) and the concentration of IL-6 and Keratinocyte Chemoattractant (KC) in LPS induced keratitis model.
  • Fig. 6 illustrates the immune-suppressing effect of topical application of OCA on the production of IL-10 in LPS-induced human skin model ex vivo.
  • Figure shows skin preparations treated with OCA gel (1%), DEX (5 pg/ml) and untreated preparations. The results are normalized to LPS-induced untreated skin (*p ⁇ 0.05).
  • Fig. 7 illustrates the same effect with the example of IL-6, , using the same system and concentrations of actives (*p ⁇ 0.02, **p ⁇ 0.01).
  • Fig. 8 illustrates the effect of OCA as a skin whitening agent.
  • Figure shows the a comparative dose response of tyrosinase activity normalized to non-treated control (%) with various concentrations of OCA and other known whitening agents such as Kojic acid, cysteine and ascorbic acid in a cell-free system.
  • DETAILED DESCRIPTION OF EMBODIMENTS
  • the present invention is essentially centered around oleylcysteineamide (OCA) which was previously recognized as an inert linker moiety for associating various active agents to a surface region of a particle carrier with no measurable biological effects, neither for OCA itself nor for an OCA-associated particle.
  • OCA oleylcysteineamide
  • OCA-associated particles, per se have proven effective active pharmaceutical ingredients (APIs) in the absence of other therapeutic agents, and thus could be applicable for treating various types of disorders and clinical or sub-clinical conditions in mammals and humans.
  • 'active pharmaceutical ingredient (API)' refers herein to the definition by WHO, i.e., 'a substance intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to have direct effect in restoring, correcting, or modifying physiological functions in human beings'.
  • the API of the invention is OCA, OCA derivative or OCA-associated nano or microparticle.
  • the term API does not encompass any therapeutically or cosmetically known active material.
  • Oleylcysteineamide has the following structure: wherein the double bond may be in a cis or trans configuration.
  • the invention can use OCT derivatives or analogues.
  • the term 'derivative' is used herein under the conventional definition to encompass any compound that is formed from a similar compound or a compound that can be imagined arising from another compound, if one atom is replaced with another atom or group of atoms.
  • the term 'analogue' (herein also 'homologue') encompasses herein any compound having a structure similar to that of another compound but differing from it in respect to a certain component (also a structural analogue or a chemical analogue).
  • the OCT derivatives or analogues can have the general structure (I): wherein each of R1 and R2, independently of the other, is a lipophilic moiety or H, provided that both R1 and R2 are not H.
  • each of R1 and R2, independnetly can be selected from -H, -Cl-C25alkyl, -C2-C25alkenyl, -C2-C25alkynyl, -C6-C10aryl and C3- ClOheteroaryl, provided that both R1 and R2 are not H.
  • R2 is H.
  • R1 is different from H.
  • R2 is H and R1 is different from H.
  • R2 is H and R1 is selected from -Cl-C25alkyl, -C2- C25alkenyl, -C2-C25alkynyl, -C6-C10aryl and C3-C10heteroaryl.
  • R2 is H and R1 is -Cl-C25alkyl or -C2-C25alkenyl.
  • the group -Cl-C25alkyl refers to a substituted or unsubstituted, linear or branched aliphatic (alkyl or alkylene) group having between 1 and 25 carbon atoms.
  • Non-limiting examples of such groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosanyl and others.
  • R1 is a group comprising one or more double bonds, thus being of the form -C2-C25alkenyl.
  • the double bond may be positioned along the chain or at the terminus and may be cis or trans. In cases where two or more double bonds are present, they both may be positioned along the chain or one may be at the terminus. They can be both cis or trans, or a mixture of the two configurations.
  • the saturated or unsaturated or fatty acid may be selected from propionic, butyric, valeric, caproic, enanthic, caprylic, pelargonic, capric, undecylic, lauric, tridecylic, myristic, pentadecylic, palmitic, margaric, stearic, nonadecylic, arachidic, heneicosylic, behenic, tricosylic, lignoceric, pentacosylic, octenoic, decenoic, decadienoic, lauroleic, laurolinoleic, myristovaccenic, myristolinoleic, myristolinolenic, palmitolinolenic, palmitidonic, a
  • the moiety R2O- is derived from an alcohol or a fatty alcohol selected from methyl, ethyl, propyl, butyl, iso-butyl tert-butyl, pentyl, tert-amyl alcohol, hexyl, 3 -methyl- 3 -pentyl, 1-heptyl, capryl, pelargonyl, decyl, capryl, undecyl, lauryl, tridecyl, myristyl, pentadecyl, cetyl, palmitoleyl, heptadecyl, stearyl, oleyl, nonadecyl, arachidyl, heneicosyl, behenyl, erucyl, and lignoceryl alcohol and others.
  • an alcohol or a fatty alcohol selected from methyl, ethyl, propyl, butyl, iso-butyl tert-butyl, penty
  • the compound is OCA.
  • R2 is H and R1 is any one of propionic, butyric, valeric, caproic, enanthic, caprylic, pelargonic, capric, undecylic, lauric, tridecylic, myristic, pentadecylic, palmitic, margaric, stearic, nonadecylic, arachidic, heneicosylic, behenic, tricosylic, lignoceric, pentacosylic, octenoic, decenoic, decadienoic, lauroleic, laurolinoleic, myristovaccenic, myristolinoleic, myristolinolenic, palmitolinolenic, palmitidonic, a-linolenic, stearidonic, dihomo-a-linolenic, eicosatetraenoic, eicosapentaenoic, clupanodonic, do
  • the OCA or the derivative or the analog can be associated with at least one carrier.
  • the at least one carrier can be a nanocarrier or a microcarrier.
  • the API of the invention consist of OCA, OCA derivative or analogue thereof as defined, or OCA associated to at least one (nano or micro) carrier as defined.
  • OCA- or OCA derivative/analogue-carrier compounds wherein either the carrier or the OCA or the derivative or the analogue are associated to another active agent.
  • compounds wherein the carrier comprises or contains or encapsulates another active agent are also excluded.
  • the nanocarrier or microcarrier is typically a nanoparticle or a microparticle.
  • Particles composed of materials approved for human or animal use are particularly applicable to the invention, such as materials listed as Generally Recognized as Safe (GRAS) under Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act, and are approved for use in microparticulate systems.
  • GRAS Generally Recognized as Safe
  • the nanoparticles or microparticles is composed of a polymeric material.
  • the polymeric material is selected from poly(lactic acid) (PEA), poly(lacto-co-glycolide) (PEG), poly(lactic glycolic) acid (PLGA), poly(lactide), polyglycolic acid (PGA), poly(caprolactone), poly(hydroxybutyrate) and/or copolymers thereof.
  • the polymeric material can be selected from PLA, PGA and PLGA.
  • the polymeric material can be PLGA.
  • the PLGA polymer is a copolymer of polylactic acid (PLA) and polyglycolic acid (PGA), the copolymer being, in some embodiments, selected amongst block copolymer, random copolymer and grafted copolymer.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • the copolymer is a random copolymer.
  • the PLGA can have an average molecular weight of between 2,000 and 100,000 Da. In other embodiments the PLGA can have an average molecular weight of between 2,000 and 7,000 Da. In other embodiments the PLGA can have an average molecular weight of between 2,000 and 5,000 Da. In still further embodiments the PLGA can have an average molecular weight of between 4,000 and 20,000 Da, or between 4,000 and 10,000 Da, or between 4,000 and 5,000 Da. In still other embodiments the PLGA can have an average molecular weight of about 2,000, about 4,500, about 5,000, about 7,000, about 10,000, about 50,000 or about 100,000 Da.
  • the nanoparticles particles can have an average diameter that is between about 10 nm and 1000 nm, and specifically between about 10-100 nm, 100-200 nm, 200-300 nm, 300-400 nm, 400-500 nm, 500-600 nm, 600-700 nm, 700- 800 nm, 800-900 nm and 900-1000 nm.
  • the microparticles can have an average diameter that is between about 10 pm and 1000 pm, and specifically between about 10-100 pm, 100- 200 pm, 200-300 pm, 300-400 pm, 400-500 pm, 500-600 pm, 600-700 pm, 700-800 pm, 800-900 pm and 900-1000 pm.
  • the OCA or the derivatives or the analogues as above can be used as APIs in treating, alleviating or preventing various types of disorders or clinical or sub-clinical conditions in mammals and humans.
  • said disorders or clinical or sub-clinical conditions that comprise inflammation.
  • said disorders or clinical or sub-clinical conditions or the inflammation can further comprise a microbial infection.
  • microbial encompasses herein bacterial, vital, fungal and other parasitic infections.
  • said “treating alleviating or preventing disorders or clinical or sub-clinical conditions” can comprise exerting an anti-inflammatory effect on the disorders or the clinical or sub-clinical conditions.
  • said exerting an anti-inflammatory effect on the disorders or the clinical or sub-clinical conditions is in the absence of other therapeutic agents, apart from the OCA or a derivative or an analogue and their surface-associated carriers as above.
  • the API is at least one of the following: (1) OCA; (2) an OCA derivative or analogue as defined herein; or (3) a carrier (e.g., nanoparticle/microparticle) surface-associated with OCA.
  • the OCA or a derivative or an analogue and their carriers can modulate an immune response.
  • modulate' encompasses here a reduction or a suppression of an immune response, or alternatively, an increase or an enhancement of an immune response.
  • compositions comprising a therapeutically effective amount of OCA or a derivative or an analogue thereof as an API.
  • OCA or a derivative or an analogue in such compositions is associated with at least one carrier.
  • said at least one carrier is a nanocarrier or a microcarrier.
  • the nanocarrier or the microcarrier is composed of a polymeric material.
  • the polymeric material is poly(lactic glycolic) acid (PLGA).
  • the OCA or a derivative or an analogue and their carriers can modulate an immune response.
  • compositions of the invention can be adapted or formulated to be suitable for various administration modes: oral, enteral, buccal, nasal, topical, transepithelial, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, intradermal and/or parenteral administration.
  • the pharmaceutical compositions of the invention can comprise at least one additional therapeutic agent in combination or admixed with the OCA or OCA derivative or analogue.
  • the at least one additional therapeutic agent can be any therapeutic or cosmetic active agent.
  • the OCA, derivative or homologue thereof or the carrier associated equivalent are not used as carriers but rather as active agents.
  • such combinations are always mixtures wherein no association is present between an API of the invention and the additional active agent.
  • OCA-associated active agents wherein the active agent is covalently associated to OCA or associated with or contained in a carrier that is associated with OCA are excluded from the present invention.
  • the at least one additional therapeutic agent can be selected from vitamins, proteins, anti-oxidants, peptides, polypeptides, lipids, carbohydrates, hormones, antibodies, monoclonal antibodies, vaccines and other prophylactic agents, diagnostic agents, contrasting agents, nucleic acids, nutraceutical agents, small molecules (molecular weight of less than 1,000 Da or less than 500 Da), electrolytes, drugs, immunological agents and any combination thereof.
  • compositions of the invention can further comprise a pharmaceutically acceptable carrier.
  • the invention provides cosmetic compositions, cosmeceutical or dermo-cosmetic compositions.
  • This type of compositions should usually include other ranges of effective doses of actives, i.e., OCA or an OCA derivative or analogue.
  • the term ' effective amount' or ' effective dose' broadly relates to an amount of the API of the invention needed to provide a desired level physiological or desirable effect, or improvement of cometic or dermatological condition.
  • 'therapeutically effective amount' broadly relates to an amount of API needed to provide a desired level physiological or clinically measurable response.
  • Analogous terms are 'therapeutic dose' or 'therapeutically effective dose ' relate to doses of API in a pharmaceutical composition or a dosage form, which can produce an improvement/ reduction of at least one symptom of a disorder, a disease or a condition.
  • the methods of the invention are applicable to disorders or clinical or sub-clinical conditions comprising an inflammation.
  • the methods of the invention are applicable to disorders or clinical or sub-clinical conditions and inflammations associated with, mediated by or comprising a microbial infection.
  • the methods of the invention involve administering OCA or a derivative or an analogue that is associated with at least one carrier.
  • said at least one carrier is a nanocarrier or a microcarrier.
  • the nanocarrier or the microcarrier is composed of a polymeric material.
  • the polymeric material is poly(lactic glycolic) acid (PLGA).
  • the OCA or the derivative or the analogue and their carriers can modulate an immune response.
  • compositions and methods of the invention are applicable.
  • One group of such conditions is various inflammatory, infectious and autoimmune disorders.
  • Non-limiting examples of inflammatory diseases that are relevant to the invention include, but not limited to, chronic inflammatory disease and acute inflammatory disease.
  • inflammatory diseases include, but not limited to inflammatory diseases associated with hypersensitivity, autoimmune diseases, infectious diseases, graft rejection diseases, allergic diseases and cancerous diseases.
  • hypersensitivity examples include, but are not limited to, Type I, Type II, Type III, and Type IV hypersensitivity, and further immediate hypersensitivity, antibody mediated hypersensitivity, immune complex mediated hypersensitivity, T lymphocyte mediated hypersensitivity and DTH.
  • Type I or immediate hypersensitivity such as asthma.
  • Type II hypersensitivity include, but are not limited to, rheumatoid diseases, rheumatoid autoimmune diseases, rheumatoid arthritis (Krenn V. et al., Histol Histopathol 2000 Jul;15 (3):791), Psoriatic Arthritis (PA), spondylitis, ankylosing spondylitis (Jan Voswinkel et al., Arthritis Res 2001; 3 (3): 189), systemic diseases, systemic autoimmune diseases, systemic lupus erythematosus (Erikson J. et al., Immunol Res 1998;17 (l-2):49), sclerosis, systemic sclerosis (Renaudineau Y.
  • vasculitises necrotizing small vessel vasculitises, microscopic polyangiitis, Churg and Strauss syndrome, glomerulonephritis, pauci-immune focal necrotizing glomerulonephritis, crescentic glomerulonephritis (Noel LH. Ann Med Interne (Paris) 2000 May; 151 (3): 178); antiphospholipid syndrome (Flamholz R. et al., J Clin Apheresis 1999;14 (4): 171); heart failure, agonist-like beta-adrenoceptor antibodies in heart failure (Wallukat G.
  • Type IV or T cell mediated hypersensitivity include, but are not limited to, rheumatoid diseases, rheumatoid arthritis (Tisch R, McDevitt HO. Proc Natl Acad Sci U S A 1994 Jan 18; 91 (2):437), systemic diseases, systemic autoimmune diseases, systemic lupus erythematosus (Datta SK., Lupus 1998; 7 (9):591), glandular diseases, glandular autoimmune diseases, pancreatic diseases, pancreatic autoimmune diseases, Type 1 diabetes (Castano L. and Eisenbarth GS. Ann. Rev. Immunol. 8:647); thyroid diseases, autoimmune thyroid diseases, Graves’ disease (Sakata S.
  • delayed type hypersensitivity examples include, but are not limited to, contact dermatitis and drug eruption.
  • T lymphocyte mediating hypersensitivity examples include, but are not limited to, helper T lymphocytes and cytotoxic T lymphocytes.
  • helper T lymphocyte-mediated hypersensitivity examples include, but are not limited to, Thl lymphocyte mediated hypersensitivity and Th2 lymphocyte mediated hypersensitivity.
  • cardiovascular diseases include, but are not limited to, cardiovascular diseases, rheumatoid diseases, glandular diseases, gastrointestinal diseases, cutaneous diseases, hepatic diseases, neurological diseases, muscular diseases, nephric diseases, diseases related to reproduction, connective tissue diseases and systemic diseases.
  • autoimmune cardiovascular diseases include, but are not limited to atherosclerosis (Matsuura E. et al., Lupus. 1998;7 Suppl 2:S 135), myocardial infarction (Vaarala O. Lupus. 1998;7 Suppl 2:S132), thrombosis (Tincani A. et al., Lupus 1998;7 Suppl 2:S107-9), Wegener’s granulomatosis, Takayasu’s arteritis, Kawasaki syndrome (Praprotnik S. et al., Wien Klin Klin Klinschr 2000 Aug 25;112 (15-16):660), anti-factor VIII autoimmune disease (Lacroix-Desmazes S.
  • autoimmune rheumatoid diseases include, but are not limited to rheumatoid arthritis (Krenn V. et al., Histol Histopathol 2000 Jul;15 (3):791; Tisch R, McDevitt HO. Proc Natl Acad Sci units S A 1994 Jan 18;91 (2):437) and ankylosing spondylitis (Jan Voswinkel et al., Arthritis Res 2001; 3 (3): 189).
  • autoimmune glandular diseases include, but are not limited to, pancreatic disease, Type I diabetes, thyroid disease, Graves’ disease, thyroiditis, spontaneous autoimmune thyroiditis, Hashimoto’s thyroiditis, idiopathic myxedema, ovarian autoimmunity, autoimmune anti- sperm infertility, autoimmune prostatitis and Type I autoimmune polyglandular syndrome.
  • Diseases include, but are not limited to autoimmune diseases of the pancreas, Type 1 diabetes (Castano L. and Eisenbarth GS. Ann. Rev. Immunol. 8:647; Zimmet P. Diabetes Res Clin Pract 1996 Oct;34 Suppl:S125), autoimmune thyroid diseases, Graves’ disease (Orgiazzi J.
  • autoimmune gastrointestinal diseases include, but are not limited to, chronic inflammatory intestinal diseases (Garcia Herola A. et al., Gastroenterol Hepatol. 2000 Jan; 23 (1): 16), celiac disease (Landau YE. and Shoenfeld Y. Harefuah 2000 Jan 16; 138 (2): 122), colitis, ileitis and Crohn’s disease.
  • autoimmune cutaneous diseases include, but are not limited to, autoimmune bullous skin diseases, such as, but are not limited to, pemphigus vulgaris, bullous pemphigoid and pemphigus foliaceus.
  • autoimmune hepatic diseases include, but are not limited to, hepatitis, autoimmune chronic active hepatitis (Franco A. et al., Clin Immunol Immunopathol 1990 Mar; 54 (3):382), primary biliary cirrhosis (Jones DE. Clin Sci (Colch) 1996 Nov; 91 (5):551 ; Strassburg CP. et al., Eur J Gastroenterol Hepatol. 1999 Jun; 11 (6):595) and autoimmune hepatitis (Manns MP. J Hepatol 2000 Aug; 33 (2):326).
  • autoimmune neurological diseases include, but are not limited to, multiple sclerosis (Cross AH. et al., J Neuroimmunol 2001 Jan 1;112 (1-2):1), Alzheimer’s disease (Oron L. et al., J Neural Transm Suppl. 1997;49:77), myasthenia gravis (Infante AJ. And Kraig E, Int Rev Immunol (1999) 18(1 -2): 83; Oshima M. et al., Eur J Immunol (1990) 20(12):2563), neuropathies, motor neuropathies (Kornberg AJ. J Clin Neurosci.
  • autoimmune muscular diseases include, but are not limited to, myositis, autoimmune myositis and primary Sjogren’s syndrome (Feist E. et al., Int Arch Allergy Immunol 2000 Sep;123 (1):92) and smooth muscle autoimmune disease (Zauli D. et al., Biomed Pharmacother 1999 Jun;53 (5-6):234).
  • autoimmune nephric diseases include, but are not limited to, nephritis and autoimmune interstitial nephritis (Kelly CJ. J Am Soc Nephrol 1990 Aug; 1 (2): 140).
  • autoimmune diseases related to reproduction include, but are not limited to, repeated fetal loss (Tincani A. et al., Lupus 1998; 7 Suppl 2:S 107-9).
  • autoimmune connective tissue diseases include, but are not limited to, ear diseases, autoimmune ear diseases (Yoo TJ. et al., Cell Immunol 1994 Aug; 157
  • autoimmune systemic diseases include, but are not limited to, systemic lupus erythematosus (Erikson J. et al., Immunol Res 1998;17 (l-2):49) and systemic sclerosis (Renaudineau Y. et al., Clin Diagn Lab Immunol. 1999 Mar;6
  • compositions and methods of the invention can be applicable for treating, alleviating and preventing systemic and local conditions and disorders.
  • they can be applicable to treatment of prevention of chronic granulomatous disease, osteoporosis, Friedreich's ataxia, moderate to severe atopic dermatitis, pulmonary fibrosis or scleroderma.
  • they can be applicable to treatment of prevention of skin diseases or skin conditions.
  • they can be applicable to treatment of prevention of hepatitis and tuberculosis.
  • they can be applicable to treatment of prevention of various types of cancer.
  • they can be applicable as an adjuvant for cancer immunotherapy.
  • they can be applicable as an adjuvant for chemotherapies.
  • they can be applicable as an adjuvant for vaccine therapies.
  • compositions and methods of the invention are applicable for treatment and prevention of disorders or clinical or sub- clinical conditions requiring modulation of an immune response.
  • said modulating an immune response comprises inducing or enhancing the immune response. Examples of such conditions are cancer, infectious diseases, inflammatory diseases, and autoimmune diseases, wherein immuno stimulatory therapy is needed to detect and eliminate non-self-antigens, and to establish memory effects for these diseases.
  • said modulating an immune response in the mammal comprises reducing or suppressing an inflammation. Examples of such conditions are overactive immune response in diseases like atherosclerosis, rheumatoid arthritis (RA), diabetes, obesity, and transplantation, immunosuppressive therapy is needed to downregulate immune reaction and generate certain immune tolerance.
  • RA rheumatoid arthritis
  • compositions and methods of the invention can modulate an immune response by modulating the production and/or secretion of at least one cytokine or a cytokine modulator.
  • said of at least one cytokine or a cytokine modulator is selected from Interferon y (INF-y), Tumor Necrosis Factor a (TNF-a), Interleukin 6 (IL-6) and Interleukin ip (IL-ip).
  • composition and methods of the invention use a binary system OCA-carrier such as OCA-PLGA-NPs (nanoparticles) for increasing or enhancing the production and/or secretion of at least one cytokine which is INF-y.
  • a binary system OCA-carrier such as OCA-PLGA-NPs (nanoparticles) for increasing or enhancing the production and/or secretion of at least one cytokine which is INF-y.
  • composition and methods of the invention use OCA alone for reducing of suppressing the production and/or secretion of at least one cytokine which can be TNF-a, IL-6 or IL-ip.
  • compositions and methods of the invention can be applied via various administration routes, including oral, enteral, buccal, nasal, topical, transepithelial, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, intradermal and/or parenteral administrations.
  • compositions and methods of the invention can include at least one additional therapeutic agent.
  • the invention can be further articulated in terms of use of OCA or the derivative or analogue and carriers as above as API in the manufacture of a medicament for treating a disorder or a clinical or sub-clinical condition in a mammal.
  • the invention provides cosmetic compositions comprising an effective amount of Oleylcysteineamide (OCA) or a derivative or an analogue thereof as an active ingredient.
  • OCA Oleylcysteineamide
  • these APIs may be formed into a lyophilized solid powder formulation that may be contained and stored as such and be ready for reconstitution in a liquid carrier upon demand.
  • the liquid carrier may be water-based carrier, for some applications (particularly those for immediate use, e.g., ophthalmic uses), or which may be an anhydrous carrier (water free), such as a silicone- based carrier, for other applications, particularly those necessitating prolonged storage periods.
  • the solid powder may alternatively be used as such, in a non-liquid or formulated form.
  • the dry powder further comprises at least one cryoprotectant that may optionally be selected from cyclodextrin, PVA, sucrose, trehalose, glycerin, dextrose, polyvinylpyrrolidone, mannitol, xylitol and others. Lyophilization may or may not be carried out in the presence of the at least one cryoprotectant.
  • a ready-for-reconstitution powder comprising an API of the invention, as disclosed, is also contemplated herein.
  • the powder may be reconstituted in a liquid carrier, as above, to form a nanoemulsion which may be stable for several weeks or over a period of time defining a treatment regimen.
  • Such products are typically for use as eye or ear products.
  • a reconstituted formulation comprising an API according to the invention is further provided, which also comprises at least one liquid carrier.
  • the liquid carrier may be water-based carrier.
  • the formulation may be for immediate use or for use within a period of between 4 and 28 days, or within a period of time to be prescribed by a medical practitioner. In some embodiments, the formulation is for prolonged use or storage.
  • such formulations are suitable as ophthalmic formulations configured for injection or as eye drops, or ear formulations, e.g., configured as eardrops.
  • APIs of the invention or compositions comprising same are suitable for skin whitening.
  • compositions can be used to provide a cosmetic antioxidative effect to the skin.
  • Such compositions are applied locally onto the skin, in other words, they should be adapted for topical or dermal administering.
  • These and also therapeutic compositions of the invention can be administered in a biocompatible aqueous or lipid solution.
  • This solution can be comprised of, but not limited to, saline, water or a pharmaceutically acceptable organic medium.
  • the cosmetic aspect can be further articulated as methods for skin whitening and/or cosmetic antioxidative effect to the skin in a subject, comprising topical and/or dermal administering to the subject the composition comprising an effective amount of OCA or the derivative or the analog as an active ingredient.
  • EXAMPLE 1 OCA-PLGA NPs conjugate enhances the production of INF-y in vivo
  • Serum interferon-y (IFN-y) levels were determined using a commercial sandwich ELISA kit (PeproTech, Rocky Hill, NJ, USA) according to the manufacturer's instructions. Outcomes were quantified by optical density at 450 nm using plate reader (Tecan, Lifesciences). Blood was drawn from NOD/SCID mice at day 29 with the indicated treatment and 5ul of serum were assayed for IFN-y levels.
  • EXAMPLE 2 OCA alone suppresses the production of IL-6 and TNF-a in vitro
  • OCA nanoemulsions were prepared at various concentrations via the well-established solvent displacement method (Fessi et al., Int. J. Pharm, 1989, 55:R1-R4).
  • OCA 10/25/50/100 mg
  • castor oil 50 mg
  • surfactant Tween 80 35mg
  • the organic phase was then poured into the aqueous phase containing Kolliphor® RH40 (50 mg).
  • the volume ratio between the organic and aqueous phases was 1:2 v/v.
  • the colloidal dispersions were stirred at 900 rpm for 15 min and concentrated by reduced pressure evaporation to 10 mL. 2.5% glycerin w/v were added to the final formulations to obtain isotonic nanoemulsions that were further filtered through 0.22pm PVDF filter before topical application.
  • the mean diameter and size distribution of the NEs were measured by Malvern's Zetasizer instrument (Nano series, Nanos-ZS) at 25°C.
  • the formulation (10 pL) was diluted in water (990pL) and measured in triplicate.
  • the size and PDI remained similar for the 4 tested concentrations respectively 110+5 nm and 0.08+0.01.
  • RAW 264.7 murine macrophage cell line purchased from American Type Culture Collection (ATCC, USA), was cultured in RPMI 1640 medium (biological industries, Israel) supplemented with 10% (v/v) of heat- inactivated fetal bovine serum and 1% antibiotics (lOO U/mL penicillin and 100 pg/mL streptomycin) and incubated at 37°C in a humidified incubator with 5% CO2. Cell that reached 80% confluency was subcultured and/or used for further experiments. The process of cell detachment involves trypsinization using trypsin enzyme (Biological Industries, Israel).
  • LPS Pseudomonas aeruginosa
  • the proinflammatory cytokines were quantified using the supernatant collected from the treated cells using ELISA (R&D Systems), and the protocol was based on the manual provided in the kit purchased.
  • the measurement of the level of cytokines involved the transferring of the collected cell culture supernatant into four separate 96- well plates coated with the capture antibody against the respective cytokine provided in the kit. The plates were read by using a microplate spectrophotometer at the absorbance of 450 nm.
  • EXAMPLE 3 OCA-PLGA NPs induce the proliferation of specific populations of immune cells in vivo
  • mice were treated once a week with PLGA-NPs and PLGA-OCA-NPs (total 3 treatments), a day after the third treatment mice peripheral venous blood was obtained from the mouse facial vein using standard techniques and analyzed using the auto hematology analyzer BC-2800 (Mindray) or an automatic Abacus Junior Vet (Diatron), following manufacturer’s instructions
  • OCA-PLGA-NPs conjugate was capable of inducing the proliferation of specific populations of immune cells, and specifically lymphocytes and monocytes as opposed to neutrophils which was specific to the OCA-PLGA-NPs treated group, but not PLGA-NPs treated or untreated controls (Fig. 4).
  • EXAMPLE 4 OCA nanoemulsions suppress inflammatory markers in a keratitis model in vivo
  • EXAMPLE 5 Topical application of OCA suppresses IL-6 and IL-ip in a keratitis model ex- vivo
  • a carbopol base gel formulation (Pemulen) was prepared to test the effect of OCA on the cytokines levels after LPS challenge on skin (ex-vzvo)/0.25 % w/v pemulen was used for preparing the base gel. Briefly, 50 mg of Pemulen was dispersed in 20 ml. DDW and mixed by an overhead stirrer, further 35pl of IM NaOH were added for obtaining the gel. Fresh OCA 1% gel, was prepared by addition of 10 mg of OCA dissolved in 25 pl ethanol to one gram of pemulen gel base, stirred to get homogenous gel. Effect of topically applied OCA gel on LPS-induced inflammatory skin model ex vivo
  • Epidermis exposed to air, was smeared with a thin layer of the test formulation, corresponding to the applied weight of 1-2 mg/cm . In 1% gel preparation, this amount contained 10-20 pg of active/cm . In the experiments, the skin piece surface was 0.25 cm , meaning 2.5-5 pg of active was topically applied to the sample.
  • the positive control 5 pg/mL of dexamethasone dissolved in 0.35 mL medium, contained 1.75 pg of the drug per sample. Untreated pieces without LPS remained as the negative control. The results were from one donor, performed with 5-6 replicates. After 24-hour treatment, cell culture medium was collected and assayed for the levels of pro- inflammatory cytokines IL-ip and IL-6 by ELISA specific kits (BioLegend).
  • EXAMPLE 6 OCA as skin-whitening agent inhibiting tyrosinase in vitro
  • Tyrosinase activity was tested in a cell-free assay as a function of DOPA oxidase activity.
  • the assay is a modification of the previously described assay (Oh et al, Ann Dermatol., 2014, 26(6):681-7).
  • To 10 pL sample (in a 96-well plate) was added 95 pl phosphate buffer saline containing 10 pg/mL mushroom tyrosinase (Worthington, Lakewood, NJ, USA, 505 U/mg). After incubations for 10 min at RT, enzymatic reaction was initiated by adding 95 pl of phosphate buffer saline containing 1 mM L- DOPA.
  • Absorbance values were measured every 5 minutes for 40 min at 475 nm using an ELISA reader at an incubation temperature of 37°C.
  • the quantity of dopachrome formed in the reaction mixture was determined against a blank (solution without enzyme) at 475 nm in the ELISA reader and expressed as a slope of the enzyme activity, measured in the linear part of the curve, normalized to the untreated control wells.
  • OCA had a similar whitening effect as Kojic acid in terms of inhibition of tyrosinase.
  • OCA can provide a potentially safe new whitening agent to be included in topical skin formulations.

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Abstract

L'objet de la présente demande concerne l'oléylcystéinamide (OCA) et des dérivés d'OCA utilisés comme agents actifs et leur utilisation dans le traitement de troubles inflammatoires ainsi que dans le traitement de blanchiment de la peau.
PCT/IL2021/050955 2020-08-06 2021-08-05 Oléylcystéinamide ou dérivés de celui-ci et leurs utilisations en thérapie WO2022029785A1 (fr)

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US18/040,450 US20230293459A1 (en) 2020-08-06 2021-08-05 Oleylcysteineamide or derivatives thereof and their use in therapy
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AU2021321510A AU2021321510A1 (en) 2020-08-06 2021-08-05 Oleylcysteineamide or derivatives thereof and their use in therapy
JP2023507990A JP2024503174A (ja) 2020-08-06 2021-08-05 オレイルシステインアミドまたはその誘導体及び治療におけるその使用
CA3190816A CA3190816A1 (fr) 2020-08-06 2021-08-05 Oleylcysteinamide ou derives de celui-ci et leurs utilisations en therapie
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